Movements of cells include contraction, migration, release, aggregation and the like, and phosphorylation of the myosin regulatory light chain is important for these cell movements. The myosin regulatory light chain is a subunit having a molecular weight of 20 kDa and constituting myosin, which exists in smooth muscle cells and various non-muscle cells such as neutrophils, platelets and nerve cells of warm-blooded animals (Non-patent document 1). Myosin existing in smooth muscle cells and various non-muscle cells such as neutrophils, platelets and nerve cells of warm-blooded animals is constituted by a myosin heavy chain subunit having a molecular weight of about 200 kDa, the myosin regulatory light chain subunit having a molecular weight of about 20 kDa, and a myosin constitutive light chain subunit having a molecular weight of about 17 kDa.
The myosin regulatory light chain is mainly phosphorylated by the myosin light chain kinase to increase the activity of myosin ATPase existing in the myosin heavy chain subunit (Non-patent document 2). It is known that the activated myosin having the increased ATPase activity becomes possible to interact with actin and activates movement apparatuses of cytoskeleton to activate cell movements. That is, it is known that activation of myosin relates to cell contraction (Non-patent document 3). It is also known that activation of myosin relates to change of cell morphology (Non-patent document 4). It is known that activation of myosin relates to cell migration (Non-patent document 5). Further, it is known that activation of myosin relates to cell release (Non-patent document 6: Kitani, S., et al., Biochem. Biophys. Res. Commun., 183, pp. 48-54, 1992). It is further known that activation of myosin relates to cell aggregation (Non-patent document 7). It is also known that activation of myosin relates to cell apoptosis (Non-patent document 8). Based on these findings, it is considered that an agent which inhibits the phosphorylation of the myosin regulatory light chain suppresses cell contraction, regulates change of cell morphology, suppresses cell migration, suppresses cell release, suppresses cell aggregation and suppresses cell apoptosis.
Cell contraction is deeply involved in diseases relating to contraction of various smooth muscle layers. Examples of such diseases include, for example, hypertension (Non-patent document 9), angina pectoris (Non-patent documents 10 and 11), cerebral vascular spasm (Non-patent documents 12, 13 and 10), erectile dysfunction (Non-patent document 14), bronchial asthma (Non-patent documents 15 and 16) and the like. Examples of the diseases relating to cell contraction also include orthopedic diseases, for example, diseases causing blood flow obstructions such as spinal canal stenosis, intervertebral disc herniation, posterior longitudinal ligament osteosis and stiffness in shoulder.
Change of cell morphology is deeply involved in diseases relating to morphological change of various cells. Examples of the diseases relating to change of cell morphology include, for example, as those relating to nerve cells of eyes, various nerve dysfunctions such as diabetic retinopathy, and glaucoma (Non-patent document 17). Further, cell migration is deeply involved in diseases relating to migration of various cells. Examples of such diseases include, for example, cancer invasion and metastasis (Non-patent documents 18 and 19), nephritis (Non-patent document 20) and the like.
Examples of diseases relating to regulation of change of cell morphology include, for example, diseases relating to nerve cells such as spinal cord injury, spinal canal stenosis, intervertebral disc herniation, intervertebral disc herniation lumbar vertebrae sequestration, lumbar vertebrae slippage, posterior longitudinal ligament osteosis, yellow ligament osteosis, Huntington disease, Parkinson's disease, amyotrophic lateral sclerosis, cerebellar ataxia, progressive supranuclear palsy, and multiple sclerosis.
Examples of diseases relating to regulation of change of cell morphology further include, for example, diseases relating to osteocytes and chondrocytes such as osteoporosis, rheumatoid arthritis, arthritis deformans, and osteogenesis imperfecta.
Furthermore, it is considered that cell release is deeply involved in various allergies and the like (Non-patent document 21), and further, cell aggregation is considered to be deeply involved in thrombosis and the like (Non-patent document 22). Further, it is known that cell apoptosis is involved in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and glaucoma, viral diseases, hepatic diseases and the like (Non-patent document 23).
Examples of the diseases relating to cell release also include inflammatory diseases relating to release of various cytokines from inflammatory cells, such as rheumatoid arthritis, acute arthritis, chronic arthritis, arthritis deformans, and multiple sclerosis.
Among orthopedic diseases, diseases relating to abnormal cell migration include bone tumors, such as bone sarcoma, enchondroma, osteoid osteoma, chondrosarcoma, chordoma, and metastatic bone tumors.
As pathways for regulating phosphorylation of myosin regulatory light chain, two pathways are known, i.e., a pathway based on activation of myosin regulatory light chain kinase induced by elevation of intracellular calcium level, and a pathway based on inactivation of myosin dephosphorylation enzyme resulting from phosphorylation of the enzyme induced by activation of Rho kinase due to activation of low-molecular-weight Rho protein (Non-patent document 24).
That is, it is considered that compounds which inhibit Rho kinase suppress cell contraction, regulate change of cell morphology, suppress cell migration, suppress cell release, suppress cell aggregation, and suppress cell apoptosis, like medicaments which inhibit phosphorylation of myosin regulatory light chain.
Based on these findings, it is considered that a substance which inhibits Rho kinase is useful as an active ingredient of a medicament for prophylactic and/or therapeutic treatment of a disease relating to cell contraction, disease relating to change of cell morphology, disease relating to cell migration, disease relating to cell release, disease relating to cell aggregation, and/or disease relating to cell apoptosis.
As agents inhibiting the phosphorylation of myosin regulatory light chain, isoquinoline derivatives are known. For example, it has been reported that 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7) inhibits the phosphorylation of myosin regulatory light chain of mesenteric artery (Non-patent document 25), and there are also known drugs inhibiting the phosphorylation of myosin regulatory light chain of iris smooth muscle (Non-patent document 26), and astrocyte (Non-patent document 27). Further, 5-substituted isoquinoline derivatives are also known (Patent document 1). However, the N atom of sulfonamide in these 5-substituted isoquinoline derivatives does not form a ring, and thus they have a structure different from that of the compounds of the present invention. Further, tricyclic compounds are also known (Patent document 2). However, these compounds are tricyclic compounds and do not have sulfonamide, and therefore they are structurally different from the compounds of the present invention.
Further, known Rho kinase inhibitors also include the amide derivatives disclosed in Patent document 3; isoquinolinesulfonyl derivatives disclosed in Patent document 4, Non-patent document 28, and Patent document 5; heterocyclic amino derivatives disclosed in Patent document 6; indazole derivatives disclosed in Patent document 7; quinazoline derivatives disclosed in Patent documents 8 and 9, and the like. However, all of these compounds are structurally different from the compounds of the present invention.    Patent document 1: International Patent Publication No. 2004/009555    Patent document 2: International Patent Publication No. 2004/108724    Patent document 3: International Patent Publication WO98/06433    Patent document 4: International Patent Publication WO97/23222    Patent document 5: International Patent Publication WO99/64011    Patent document 6: International Patent Publication WO01/56988    Patent document 7: International Patent Publication WO02/100833    Patent documents 8: International Patent Publication WO02/076976    Patent documents 9: International Patent Publication WO02/076977    Non-patent document 1: Barany, K., et al., Biochemistry of Smooth Muscle Contraction, pp. 21-35, 1996    Non-patent document 2: Barany, M., et al., Biochemistry of Smooth Muscle Contraction, pp. 321-339, 1996    Non-patent document 3: Kamm, K., et al., Annu. Rev. Physiol., 51, pp. 299-313, 1989    Non-patent document 4: Schmidt, J. T. et al., J, Neurobiol., 52 (3), pp. 175-188, 2002    Non-patent document 5: Niggli, V., FEBS Lett., 445, pp. 69-72, 1999    Non-patent document 6: Kitani, S., et al., Biochem. Biophys. Res. Commun., 183, pp. 48-54, 1992    Non-patent document 7: Itoh, K., et al., Biochim. Biophys. Acta., 1136, pp. 52-56, 1992    Non-patent document 8: Mills, J. C. et al., J. Cell Biol., Vol. 140, No. 3, pp. 627-636,    Non-patent document 9: Samlyo, A. P., et al., Rev. Physiol. Biochem. Pharmacol., Vol. 134, pp. 209-34, 1999    Non-patent document 10: Shimokawa et al., Cardiovasc. Res., Vol. 43, No. 4, pp. 1029-39, 1999    Non-patent document 11: Satoh, H., et al., Jpn. J. Pharmacol., 79 (suppl.), p. 211, 1999    Non-patent document 12: M. Satoh et al., the 57th General Meeting of Japan Neurosurgical Society, Collection of Abstracts, 153, 1998    Non-patent document 13: N. Ono et al., Pharmacol. Ther., Vol. 82, No. 2-3, pp. 123-31,    Non-patent document 14: Andersson, K E. et al., World J. Vrol., 15, pp. 14-20, 1997    Non-patent document 15: K. Iidzuka, Allergy, 47, 943, 1998    Non-patent document 16: K. Iidzuka et al., Jpn. J. Respirology Society, 37, 196, 1999    Non-patent document 17: Arakawa, Y., et al., BIO Clinica, 17 (13), pp. 26-28, 2002    Non-patent document 18: Itoh, K. et al., Nat. Med., Vol. 5, No. 2, pp. 221-5, 1999    Non-patent document 19: Keely, P. et al., Trends Cell Biol., Vol. 8, No. 3, pp. 101-6,    Non-patent document 20: Fujimoto, O. et al., Journal of Japanese Society of Internal Medicine, 88 (1), pp. 148-58, 1998    Non-patent document 21: Keane-Myers A. et al., Curr. Allergy Asthma Rep., 1(6):550-557, 2001    Non-patent document 22: Nakai, K. et al., Blood, Vol. 90, No. 10, pp. 3736-42, 1997    Non-patent document 23: Thompson, C. B., Science, Vol. 267, pp. 1456-1462, 1995    Non-patent document 24: Fukata, Y., et al., Trends Pharmacol. Sci., 22, pp. 32-39,    Non-patent document 25: Suzuki, A. et al., Br. J. Pharmacol., 109, pp. 703-712, 1993    Non-patent document 26: Howe, P. H. et al., Biochem J., 255, pp. 423-429, 1988    Non-patent document 27: Mobley P. L., et al., Exp. Cell Res., 214, pp. 55-66, 1994    Non-patent document 28: Uehata, M. et al., Nature, 389, pp 990-994, 1997